Molecular Medicine最新文献

{"title":"COX-2 inhibition as a therapeutic strategy for bone loss in Staphylococcus aureus osteomyelitis.","authors":"Yuhui Chen, Chao Li, Jishan Jia, Yuhui Jiang, Ping Zhang, Caiyu Cheng, Guangyan Zhang, Lang Gao, Xiang Yang, Jiawei Zhao, Kaiqun Li, Bin Yu","doi":"10.1186/s10020-025-01202-9","DOIUrl":"https://doi.org/10.1186/s10020-025-01202-9","url":null,"abstract":"<p><p>Bone loss in Staphylococcus aureus (S. aureus) osteomyelitis poses a serious challenge to orthopedic treatment, but the underlying mechanism of systemic osteoporosis caused by chronic infection is not completely clear. In this study, γ-irradiation-killed S. aureus (IKSA) was applied to simulate the inflammation and explore the mechanism of systemic bone loss caused by it. In this study, we found that the systemic application of IKSA caused bone loss in mice through increasing osteoclasts and decreasing osteoblasts. An immune response profile with up-regulated COX-2 is identified based on our transcriptional data from IKSA mice bone marrow cells. COX-2 expression is widely up-regulated in bone marrow immune cells, such as myeloid-derived suppressor cells (MDSCs), neutrophils and macrophages in the IKSA-treated mice. Mechanistically, COX-2 stimulated the increasing proportion of MDSCs and neutrophils and the inflammatory response of the bone marrow immune cells, that may regulate bone metabolism. Importantly, COX-2 inhibitor, celecoxib could rescue the bone loss induced by IKSA, which may reason from decrease of inflammatory gene expression in MDSCs, neutrophils and macrophages. Excitingly, COX-2 expression is also increased in bone marrow from mice and patients with S. aureus osteomyelitis. These findings suggested a therapeutic potential for inhibiting COX-2 in combating bone loss in S. aureus osteomyelitis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"177"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced potency of immune checkpoint inhibitors against poorly immunological solid tumors by immune stimulatory oncolytic adenoviruses-mediated remodeling of the tumor microenvironment.","authors":"Hyo Min Ahn, Bo-Kyeong Jung, JinWoo Hong, Dayoung Hong, A-Rum Yoon, Chae-Ok Yun","doi":"10.1186/s10020-025-01223-4","DOIUrl":"https://doi.org/10.1186/s10020-025-01223-4","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) have shown promising results against a variety of solid tumors across clinical trials. However, ICI monotherapy is often ineffective in patients with non-immunogenic tumors that exhibit high level of immunosuppression and low level of tumor infiltrating lymphocytes. To address these limitations, we have investigated a combination of ICIs [anti-PD-1 antibody (αPD-1), anti-PD-L1 antibody (αPD-L1), or anti-CTLA-4 antibody (αCTLA-4)] with several different immune stimulatory oncolytic adenoviruses (Ads) expressing different combinations of antitumor cytokines or immune modulatory factors [e.g., (1) interleukin (IL)-12 and granulocyte-macrophage colony-stimulating factor (GM-CSF; RdB/IL12/GMCSF), (2) IL-12 and short hairpin ribonucleic acid (shRNA) targeting vascular endothelial growth factor (RdB/IL12/shVEGF), (3) IL-12 and decorin (RdB/IL12/DCN), (4) GM-CSF, and thymidine kinase (RdB/IL12/GMCSF-TK), or (5) IL-12, GM-CSF, and relaxin (RdB/IL12/GMCSF-RLX)] to overcome tumor-induced immunosuppression. Through comparative evaluation of combination therapy regimens, our findings have identified αPD-1 as the optimal ICI candidate to synergize with different oncolytic Ads to induce potent antitumor immune response against poorly immunological solid tumors.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"175"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin alleviates sepsis-induced acute lung injury by inhibiting necroptosis via reducing circulating mtDNA release.","authors":"Yuce Peng, Jia Xu, Lingyu Wei, Minghao Luo, Shenglong Chen, Xuebiao Wei, Suxin Luo, Zedazhong Su, Zhonghua Wang","doi":"10.1186/s10020-025-01228-z","DOIUrl":"https://doi.org/10.1186/s10020-025-01228-z","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a life-threatening condition that often leads to severe complications, including acute lung injury (ALI), which carries high morbidity and mortality in critically ill patients. Melatonin (Mel) has shown significant protective effects against sepsis-induced ALI, but its precise mechanism remains unclear.</p><p><strong>Methods: </strong>A cecal ligation and puncture (CLP) model was used to induce sepsis in male C57BL/6 mice, which were divided into four groups: Control, Sham, CLP, and CLP + Mel. ALI severity was evaluated via hematoxylin and eosin (H&E) staining, lung wet/dry ratio, and serum biomarkers (SP-D, sRAGE). Inflammatory cytokines (IL-1β, IL-6, TNF-α) were measured in serum and bronchoalveolar lavage fluid using ELISA. Circulating mitochondrial DNA (mtDNA) subtypes (D-loop, mt-CO1, mMito) were quantified by real-time PCR. TUNEL staining was performed to assess lung cell apoptosis. Necroptosis and STING pathway activation were analyzed via Western blot and immunofluorescence.</p><p><strong>Results: </strong>Sepsis led to increased circulating mtDNA levels and activation of necroptosis signaling pathways. Melatonin treatment alleviated sepsis-induced ALI, improving survival, reducing inflammatory cytokines and mtDNA release, and suppressing necroptosis. Intraperitoneal injection of mtDNA in mice activated necroptosis, while RIP1 inhibitor Nec-1 counteracted mtDNA-induced lung damage and necroptosis in sepsis-induced ALI. Additionally, melatonin significantly inhibited STING pathway activation. Further experiments revealed that STING modulation influenced necroptosis protein expression and mediated melatonin's protective effects in sepsis-induced ALI.</p><p><strong>Conclusion: </strong>Melatonin mitigates sepsis-induced ALI by suppressing necroptosis through inhibition of STING activation and reduction of mtDNA release. These findings suggest melatonin as a potential therapeutic strategy for sepsis-induced ALI.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"176"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pilot study on the effect of SARS-CoV-2 spike protein on IL-1β-mediated inflammation in peripheral blood immune cells from AIED patients.","authors":"Shresh Pathak, Natalie Tan, Andrea Vambutas","doi":"10.1186/s10020-025-01227-0","DOIUrl":"https://doi.org/10.1186/s10020-025-01227-0","url":null,"abstract":"<p><strong>Background: </strong>Immune-mediated hearing loss (IMHL) patients (comprised of autoimmune inner ear disease (AIED) and sudden sensorineural hearing loss (SSNHL)) may be at higher risk for hearing loss following Coronavirus disease (COVID-19) infection and/or vaccination.</p><p><strong>Methods: </strong>We compared inflammatory cytokine expression in response to SARS-CoV2 spike protein between two groups of patients with IMHL: IMHL patients that temporally demonstrated worsening SNHL following COVID vaccination or infection as compared to IMHL patients with worsening SNHL unrelated to COVID exposure: (IMHL-COVID ( +)) (n = 11) (IMHL-COVID (-)) (n = 10). In these two groups, we treated isolated PBMCs with increasing amounts of SARS-CoV-2 spike protein and compared responses to stimulation with positive and negative controls.</p><p><strong>Results: </strong>Peripheral Blood Mononuclear Cells (PBMC) from IMHL-COVID ( +) patients had increased expression and release of both IL-1β and IL-6 in response to spike protein as compared to IMHL-COVID (-) patients. However, when the IMHL-COVID ( +) group was broken down into AIED patients compared to SSNHL, it became apparent that the greatest responses were from the AIED patients (p < 0.005 for IL-6 mRNA expression and p < 0.003 for IL-6 release when compared between any two similar groups using Wilcoxon Rank-Sum Test). When we broke down the COVID ( +) group to infection versus vaccination, the immune responses in the infection group (N = 3 AIED, 1 SSNHL) were stronger.</p><p><strong>Conclusions: </strong>COVID-19 exposure with reported changes in hearing sensitivity in IMHL patients resulted in pro-inflammatory responses in response to spike protein. The inflammatory responses were greatest in AIED patients, and greater following infection rather than vaccination. Therefore, based on these studies, we would recommend AIED patients take additional precautions to avoid COVID exposure. Furthermore, we do recommend COVID vaccination during periods of hearing stability, as the immune responses are even more robust in response to infection in this vulnerable group.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"174"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes derived from human amniotic mesenchymal stem cells promotes angiogenesis in hUVECs by delivering novel miRNA N-194.","authors":"Yang Song, Tao Zhang, Ping Shi, Yingzhuo Gao, Xining Pang","doi":"10.1186/s10020-025-01192-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01192-8","url":null,"abstract":"<p><strong>Background: </strong>To investigate the effect and mechanism of exosomes derived from human amniotic mesenchymal stem cells (hAMSC-Exos) promoting angiogenesis.</p><p><strong>Methods: </strong>HAMSC-Exos were isolated using ultracentrifugation and characterized by transmission electron microscopy, NTA, and Western blot. The uptake of hAMSC-Exos by hUVECs was analyzed using PKH-26 labeling, and the effect of hAMSC-Exos on angiogenesis was analyzed in human umbilical vein endothelial cells hUVECs by cell viability assay, Transwell migration assay, Matrigel tube formation assay, and Matrigel plug assays in nude mice. Bioinformatics methods were used to analyze miRNA high-throughput sequencing data of hAMSC-Exos, and RT-qPCR was used to validate the novel miRNAs. HAMSC-Exos with high and low N-194 expression were obtained by transfection, respectively. Target genes were predicted using TargetScan, and the mRNA and protein levels of potential target genes were analyzed by RT-qPCR and Western blot after N-194 mimics transfection. Interaction between miRNAs and target genes was detected using the dual-luciferase reporter assay. Target genes were overexpressed in hUVECs by transfection. The roles of target genes in the influence of N-194 on cell function were determined by analyzing angiogenesis.</p><p><strong>Results: </strong>The extracted hAMSC-Exos showed saucer-shaped under transmission electron microscopy, and the NTA results showed the particle size of 115.6 ± 38.6 nm. The positive expression of CD9, CD63, and CD81 were verified using Western blot. The treatment of hUVECs with hAMSC-Exos significantly increased cell proliferation, migration, and angiogenesis. HAMSC-Exos contained the novel miRNAs N-194, N-314, N-19, N-393, and N-481, and the expression of N-194 was higher. The Exos derived from hAMSCs which were transfected with FAM-N-194 mimics were able to deliver FAM-N-194 mimics to hUVECs. The hAMSC-Exos with high N-194 significantly promoted angiogenesis in hUVECs. N-194 mimics transfection significantly reduced mRNA and protein levels of potential target gene ING5, and N-194 mimics significantly reduced the luciferase activities expressed by wild-type reporter gene vectors for ING5. The ING5 overexpression significantly reduced the angiogenic capacity of hUVECs. ING5 overexpression suppressed the expression of HSP27 and PLCG2.</p><p><strong>Conclusions: </strong>HAMSC-Exos promotes angiogenesis in hUVECs by delivering novel miRNA N-194 which targets ING5.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"173"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paclitaxel alleviates spinal cord injury via activation of the Wnt/β-catenin signaling pathway.","authors":"Zhifeng Chen, Da Wo, Celiang Wu, En Ma, Jinhui Peng, Weidong Zhu, Dan-Ni Ren","doi":"10.1186/s10020-025-01240-3","DOIUrl":"https://doi.org/10.1186/s10020-025-01240-3","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) is a disability that causes severe traumatic damage to the central nervous system, with increasing prevalence worldwide. Paclitaxel (PTX) is a naturally occurring plant metabolite that has been shown to exhibit various neuroprotective effects in the central nervous system, however, the specific mechanisms underlying its protective effects in SCI remain unclear. In this study, we aimed to explore the therapeutic effects of PTX in SCI, as well as elucidate the underlying molecular mechanisms associated with its neuroprotective potential.</p><p><strong>Methods: </strong>Murine models of spinal cord compression were performed followed by intrathecal administration of corresponding agents for 21 days. Mice were randomly divided into the following four groups: Sham, SCI + Saline, SCI + PTX, and SCI + PTX + XAV939. Recovery of lower limb function and strength, as well as muscular atrophy were examined via multiple scored tests. Degree of neuronal and axonal damage, as well as fibrosis were examined via immunohistochemical staining.</p><p><strong>Results: </strong>PTX administration significantly improved the recovery of lower limb function and strength, prevented muscular atrophy, as well as decreased the extent of neuronal and axonal death following SCI surgery. PTX also robustly activated the Wnt/β-catenin protein signaling pathway that played a key role in its therapeutic effects. Co-administration with a Wnt/β-catenin pathway inhibitor - XAV939, significantly abolished the beneficial effects of PTX after SCI.</p><p><strong>Conclusion: </strong>This study provides important new mechanistic insight on the beneficial effects of PTX in protecting against spinal cord injury, as well as the experimental basis for its potential therapeutic use.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"172"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12053863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the roles of extracellular vesicles in cardiovascular diseases: pathophysiological mechanisms, biomarkers, and cell-free therapeutic strategy.","authors":"Mengyang Wang, Yuwu Chen, Biyi Xu, Xinxin Zhu, Junke Mou, Jiani Xie, Ziao Che, Liyang Zuo, Ji Li, Haibo Jia, Bo Yu","doi":"10.1186/s10020-025-01200-x","DOIUrl":"https://doi.org/10.1186/s10020-025-01200-x","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) represent a profound challenge with inflammation playing a significant role in their pathophysiology. Extracellular vesicles (EVs), which are membranous structures encapsulated by a lipid bilayer, are essential for intercellular communication by facilitating the transport of specific bioactive molecules, including microRNAs, proteins, and lipids. Emerging evidence suggests that the regulatory mechanisms governing cardiac resident cells are influenced by EVs, which function as messengers in intercellular communication and thereby contribute to the advancement of CVDs. In this review, we discuss the multifaceted biological functions of EVs and their involvement in the pathogenesis of various CVDs, encompassing myocardial infarction, ischemia-reperfusion injury, heart failure, atherosclerosis, myocarditis, cardiomyopathy, and aneurysm. Furthermore, we summarize the recent advancements in utilizing EVs as non-invasive biomarkers and in cell-free therapy based on EVs for the diagnosis and treatment of CVDs. Future research should investigate effective techniques for the isolation and purification of EVs from body fluids, while also exploring the pathways for the clinical translation of therapy based on EVs. Additionally, it is imperative to identify appropriate EV-miRNA profiles or combinations present in the circulation of patients, which could serve as biomarkers to improve the diagnostic accuracy of CVDs. By synthesizing and integrating recent research findings, this review aims to provide innovative perspectives for the pathogenesis of CVDs and potential therapeutic strategies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"169"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacteriophage-derived endolysins restore antibiotic susceptibility in β-lactam- and macrolide-resistant Streptococcus pneumoniae infections.","authors":"Niels Vander Elst, Kristine Farmen, Lisa Knörr, Lotte Merlijn, Federico Iovino","doi":"10.1186/s10020-025-01226-1","DOIUrl":"https://doi.org/10.1186/s10020-025-01226-1","url":null,"abstract":"<p><p>Streptococcus pneumoniae, the pneumococcus, is a cause of major illness globally. Invasive pneumococcal disease (IPD) is characterized by pneumococci invading blood (bacteremia), lungs (pneumonia), or brain and cerebrospinal fluid (meningitis). Meningitis remains an important global health concern because half of the survivors experience long-term neurological damage. The antibiotics commonly used to treat pneumococcal infections are β-lactams and macrolides, however, S. pneumoniae is nowadays often resistant to one or several antibiotics, therefore novel antimicrobials are needed. Here, we found that the bacteriophage-derived cpl-1 endolysin showed consistent antibacterial activity against β-lactam- and macrolide-resistant pneumococcal clinical strains grown in human blood and human cerebrospinal fluid. Exploiting synergistic and additive mechanisms, supplementation of cpl-1 to either penicillin or erythromycin, as representatives for β-lactam and macrolide antibiotics, rescued human neuronal cells from the cytotoxicity of antibiotic-resistant pneumococcal infections. Finally, systemic administration of cpl-1 supplemented to penicillin in mice infected with penicillin-resistant pneumococci successfully reduced bacteremia, and, thanks to the efficient penetration across the blood-brain barrier, abolished bacterial load in the brain, resulting in increased (89%) survival accompanied by an asymptomatic course of infection. These findings strongly suggest that cpl-1 can enhance antibiotic susceptibility in β-lactam- and macrolide-resistant S. pneumoniae, serving as a valuable adjunct therapy to standard-of-care antibiotics for multidrug-resistant IPD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"170"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of TLR4 mitigates sensorineural hearing loss resulting from cochlear inflammation.","authors":"Jintao Lou, Fan Wu, Wei Liu, Rui Hu, Wuhui He, Yisi Feng, Yan Huang, Jia Guo, Jingman Deng, Zhen Zhao, Zhigang Zhang, Yu Si","doi":"10.1186/s10020-025-01219-0","DOIUrl":"https://doi.org/10.1186/s10020-025-01219-0","url":null,"abstract":"<p><strong>Background: </strong>Inflammation is a principal cause of sensorineural hearing loss resulting from cochlear injury. However, current research investigating the mechanisms of sensorineural inflammatory injury remains inadequate.</p><p><strong>Methods: </strong>Cochlear inflammation was induced by administering lipopolysaccharide (LPS) into the otic bulla (OB) and posterior semicircular canal (PSCC). Auditory brainstem responses (ABR) were recorded, and cochlear tissue alterations were analyzed using hematoxylin and eosin (HE) staining and immunofluorescence. Levels of cochlear inflammation were quantified using a cytokine array. Additionally, Toll-like receptor 4 (TLR4) knockout mice were employed to evaluate sensorineural neuroprotection.</p><p><strong>Results: </strong>LPS injection into the PSCC caused more pronounced and stable cochlear inflammatory damage compared to injection into the OB. LPS exposure led to significant loss of cochlear hair cells, atrophy of the stria vascularis, and spiral ganglion damage. Furthermore, LPS treatment upregulated TLR4 receptor expression, increased the number of Ionized calcium-binding adapter molecule 1 (IBA1) positive cells, and elevated levels of inflammatory cytokines in the cochlea. TLR4 knockout (TLR4-KO) mice demonstrated reduced LPS-induced cochlear sensorineural damage.</p><p><strong>Conclusion: </strong>LPS injection into the PSCC induces sensorineural tissue damage in the cochlea and results in sensorineural hearing loss. These findings suggest that TLR4 inhibition can alleviate cochlear inflammation-induced sensorineural hearing loss. TLR4 represents a potential therapeutic target for sensorineural hearing loss.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"168"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug screening targeting TREM2-TYROBP transmembrane binding.","authors":"M Cobas-Carreño, A Esteban-Martos, L Tomas-Gallardo, I Iribarren, L Gonzalez-Palma, A Rivera-Ramos, J Elena-Guerra, E Alarcon-Martin, R Ruiz, M J Bravo, J L Venero, X Morató, A Ruiz, J L Royo","doi":"10.1186/s10020-025-01229-y","DOIUrl":"https://doi.org/10.1186/s10020-025-01229-y","url":null,"abstract":"<p><p>TREM2 encodes a microglial membrane receptor involved in the disease-associated microglia (DAM) phenotype whose activation requires the transmembrane interaction with TYROBP. Mutations in TREM2 represent a high-impact risk factor for Alzheimer's disease (AD) which turned TREM2 into a significant drug target. We present a bacterial two-hybrid (B2H) system designed for high-throughput screening of modulators for the TREM2-TYROBP transmembrane interaction. In a pilot study, 315 FDA-approved drugs were analyzed to identify potential binding modifiers. Our pipeline includes multiple filtering steps to ensure candidate specificity. The screening suggested two potential candidates that were finally assayed in the human microglial cell line HMC3. Upon stimulation with anti-TREM2 mAb, pSYK/SYK ratios were calculated in the presence of the candidates. As a result, we found that varenicline, a smoking cessation medication, can be considered as a transmembrane agonist of the TREM2-TYROBP interaction.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"171"},"PeriodicalIF":6.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}